Previously, we obtained gene expression profiles of primary prostate tumors resected from 33 African-American and 36 European-American patients. Analyzing the resulting datasets, we identified gene expression differences between African-American and European-American patients that portray the existence of a distinct tumor microenvironment for these two patient groups. Many of the differently expressed genes were immune-regulatory. Perhaps most significant was the presence of a distinct interferon signature in many of the African-American tumors. As now discovered by us, this signature is almost identical with an interferon-related DNA damage resistance signature (IRDS) that predicts resistance to chemotherapy and radiation. The presence of IRDS in African-American tumors may not only affect the response of them to immune-based therapies but may also make them more resistant to standard therapy including radiation therapy. In addition, IRDS has been linked to the pro-metastatic epithelial to mesenchymal transition of cancer cells and is induced by interactions between fibroblasts and tumor cells. Thus, IRDS may also promote the metastatic process. We completed very recently the analysis of two independent datasets with gene expression profiles from African-American and European-American tumors, which showed that IRDS is significantly more common in tumors from the African-American patients than in tumors from European-American patients in both datasets. To explore the origin of IRDS, we interrogated the expression profiles of isolated primary human prostate epithelial cells from 14 African-American patients and 13 European-American patients for the presence of IRDS. This analysis led to the finding that IRDS is present in these cultured cells, thus persisting in cancer cells after being removed from the tumor microenvironment, and was observed in 5 out of 14 (36%) isolates from African-American patients versus 2 out of 13 (15%) isolates from European-American patients. We believe that the heightened prevalence of IRDS in cancer cells from African-American patients could be clinically very significant and warrants further investigations into the origin of this signature, and also how this signature can be targeted. To further understand the possible origin of the detected immunobiological differences in tumors of African-American and European-American prostate cancer patients, we started with the evaluation of blood-based immune cell profiles of African-American and European-American prostate cancer patients and age-matched population-based controls with a focus of subpopulation that have immune-regulatory functions in cancer biology. It was the hypothesis of this project that immune cell subpopulation that have immune-regulatory functions in cancer biology are different in abundance in these two population groups. This project has been completed in FY13. We did not observe that any of the investigated immune cell subpopulations (myeloid-derived suppressor cells, T- and B-cell-derived suppressor cells, dendritic cell subpopulations and polarized macrophages) was different in abundance comparing the blood samples from African-American and European-American prostate cancer patients. Currently we are investigating whether the development of this signature could be functionally linked to a germline variation that frequently occurs in men of African ancestry but is rather uncommon in men of European ancestry and encodes a novel interferon termed interferon lambda 4. The presence of an interferon gene signature in prostate tumors suggests a possible involvement of either a viral infection in disease pathology or the reactivation of endogenous retroviruses in the tumor microenvironment. This hypothesis was further supported by our finding that the interferon signature in prostate tumors coincides with a gene signature of retroviral activation. Thus, we started a project exploring the presence of viral infections and the reactivation of endogenous retroviruses in tumors from African-American and European-American patients. Aberrant expression of subgroup k human endogenous retroviruses (HERV-K) has been previously observed in prostate cancer. This subgroup is unique because it encodes sequences in the human genome containing open reading frames for near intact retroviruses. We hypothesized that HERV-K reactivation could serve as a non-invasive early disease detection marker for prostate cancer. We evaluated HERV-K gag mRNA expression in blood samples of African-American and European-American men using a case-control design via quantitative real-time PCR. Additionally, we examined HERV-K envelope protein expression in prostate tumors by immunohistochemistry. HERV-K envelope protein was commonly up-regulated in prostate tumors, but more so in tumors of African-American than European-American patients (61% versus 40%). Examining HERV-K gag expression in peripheral blood mononuclear cells (PBMC) from 294 cases and 135 healthy men, we found that the abundance of HERV-K gag message was significantly higher in cases than controls and was associated with increased plasma interferon gamma. Men with gag expression in the highest quartile had 12-fold increased odds (odds ratio = 12.87 [95% confidence interval 6.3-26.25]) of being diagnosed with prostate cancer than those in the lowest quartile. Moreover, our results showed that HERV-K expression may perform better as a disease biomarker in older than younger men (whereas the sensitivity of prostate-specific antigen (PSA) testing decreases with age) and in men with a smoking history compared with never smokers. We conclude that combining non-invasive HERV-K testing with PSA testing may improve the efficacy of prostate cancer detection specifically among older men and smokers who tend to develop a more aggressive disease.